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Correlation of morphologic and moleculargenetic features of selected tumors
Šíma, Radek ; Skálová, Alena (advisor) ; Boudová, Ludmila (referee) ; Ehrmann, Jiří (referee)
We present a series of 16 salivary gland tumors with histomorphological and immunohistochemical features reminiscent of secretory carcinoma of the breast. This is a hitherto undescribed and distinctive salivary gland neoplasm, with features resembling both salivary acinic cell carcinoma and low grade cystadenocarcinoma, as well as displaying strong similarities to breast secretory carcinoma. Microscopically, the tumors have a lobulated growth pattern and are composed of microcystic and glandular spaces with abundant eosinophilic homogenous or bubbly secretory material positive for PAS, mucicarmine, MUC1, MUC4 and mammaglobin. The neoplasms also show strong vimentin, S-100 protein, and STAT5a positivity. For this tumor we propose a designation mammary analogue secretory carcinoma of salivary glands (MASC). The 16 patients comprised 9 men and 7 women, with a mean age of 46 years (range 21-75). Thirteen cases occurred in the parotid gland, and one each in the minor salivary glands of the buccal mucosa, upper lip, and palate. The mean size of the tumors was 2.1 cm (range 0.7 to 5.5 cm). The duration of symptoms was recorded in 11 cases and ranged from 2 months to 30 years. Clinical follow-up was available in 13 cases, and ranged...
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BCS (Biopharmaceutical information system) and in vitro/in vivo correlation of bioequivalent studies
Ćmiel, Radek ; Doležal, Pavel (referee) ; Tilšer, Ivan (advisor)
Biopharmaceutical classification system is a scientific framework for classifying a drug substance in to the groups based on its aqueous solubility and intestinal permeability. When combined with the in vitro dissolution characteristics of the drug product, then there are three major factors: solubility, intestinal permeability and dissolution rate. All these three factors correspond closely with the rate and extent of oral drug absorption from IR solid oral- dosage forms. This work presents the overview about the BCS from two major points of view, from the site of the World health organization (WHO) and U.S. Food and drug administration (FDA), while the FDA guideline for biowaiver is fully cited in Czech language. Also reflection of in vitro in vivo correlations in IR drugs development according to BCS is mentioned. Further, the thesis is analyzing the bioequivalence studies of Czech pharmaceutical company Zentiva, k. s. in context of BCS and compares the results with data obtained from the Canadian CRO Anapharm, which is a contract partner of many pharmaceutical companies being engaged in a clinical research and bioequivalence studies. Keywords: Biopharmaceutical classification system, solubility, permeability, dissolution, in vivo/in vitro correlations, Caco-2 cells, bioequivalence, IR drug...
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The Mode of Catecholamine Adrenergic Action in Human Peripheral Mononuclear Blood Cells
MIKULKA, Aleš
Effects of {$\alpha$}1, {$\alpha$}2, {$\beta$}3 adrenergic agonists on resting oxygen consumption and effects of {$\alpha$} and {$\beta$}2 adrenergic antagonists on noradrenaline stimulated oxygen consumption of the human peripheral blood mononuclear cells (PBMC) were studied using the Clark oxygen electrode. It was found that, the {$\alpha$}2 agonist increases slightly the resting oxygen consumption in the PBMC while, the {$\beta$}2 and the {$\alpha$} antagonists inhibit the noradrenaline stimulated oxygen consumption considerably. The {$\alpha$}1 and {$\beta$}3 agonists have no effect on the resting oxygen consumption. The NA termogenesis in the PBMC is mediated by {$\beta$}1 (25%), {$\beta$}2 (8%) and {$\alpha$}2 (12%) adrenergic receptors and not by {$\beta$}3 adrenoreceptors. The NA thermogenesis in the PBMC is mediated by different adrenoreceptors than the NA thermogenesis in the brown adipose tissue. The NA thermogenesis of PBMC is independent on the presence of organic substrates in the cultivation medium. Administration of external substrates (glucose, glutamine, methionine) to the medium has no effect on resting and NA stimulated oxygen consumption of PBMC, while administration of cysteine increases NA stimulated oxygen consumption considerably, indicating that acetyl-CoA could be an important substrate for NA thermogenesis in PBMC.
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Cyclophosphamide effects on hematopoiesis
Renešová, Nicol ; Šefc, Luděk (advisor) ; Klevstigová, Martina (referee)
Cyclophosphamide is an alkylating agent developed in the 1960s for the use in treatment of cancerous diseases. Since its introduction, it has manifested various spectra of effects. Of uttermost importance are the impacts cyclophosphamide has on the hematopoietic system housed in the bone marrow of femoral and other bones. Hematopoiesis is a complex process which has been extensively studied for decades. The more it is known about the niches the hematopoietic stem cells occupy as well as of their life cycle, the more it is possible to design functional therapy for its malignancies and improve the survival rates. The effects of cyclophosphamide administration on hematopoietic system are divided into three major cathegories: myeloablation and myelosuppression, immunosuppression, and mobilisation of hematopoietic stem cells into the peripheral blood. The immunosuppression is achieved by systematic depletion of progenitors differentiating into lecocytes. Induced neutropenia and lymphopenia allow for management of autoimmune diseases and preservation of transplants. Mobilisation, a process opposite to stem cell homing, seems to be dependent on disruption of cellular adhesion (CRXCR4/SDF-1, VCAM-1/VLA-4) facilitated by proteases released into the environment after cyclophosphamide exposure.
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Synthesis and evaluation of transdermal permeation enhancers based on terpenes
Kopečná, Monika ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Monika Kopečná Synthesis and evaluation of transdermal permeation enhancers based on terpenes Transdermal drug delivery has many advantages over the conventional routes of administration. It could make a treatment of some diseases more acceptable for patients. Other advantage is a possibility of easy interruption of treatment in case of problems. And profit comes also from the fact that the drug doesn't pass through the gastro-intestinal tract, so it avoids the first-pass effect and doesn't irritate this tract, too. But majority of drugs cannot cross the skin in sufficient amounts. To enable permeation of more drugs through the human skin, substances called transdermal permeation enhancers are used among others, some natural terpenes and amino acid derivatives such as dodecylester of 6-(dimethylamino)hexanoic acid (DDAK) are potent permeation enhancers (1) (2). The purpose of my work was to combine these potent enhancers and prepare esters of 6-(dimethylamino)hexanoic acid with selected terpenes (menthol, citronellol, linalool, farnesol and borneol) and determine their permeation-enhancing activity in vitro using two model drugs (theophylline and hydrocortisone), human skin and Franz diffusion cell. DDAK was able to increase skin flux of theophylline and hydrocortisone 23 and 37 times,...
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New pharmacological interventions influencing food intake regulation
Špolcová, Andrea ; Čabala, Radomír (advisor) ; Podlipná, Radka (referee)
NEW PHARMACOLOGICAL INTERVENTIONS INFLUENCING FOOD INTAKE REGULATION Author: Bc. Andrea Špolcová ABSTRACT Prolactin-releasing peptide (PrRP) identified as an endogenous ligand of the orphan receptor GPR10 was originally found to stimulate the secretion of prolactin (PRL) both in vitro and in vivo. PrRP-mediated PRL secretion was later questioned and is not currently considered to be the primary function of PrRP. The fact that both PrRP and GPR10 knock-out mice are hyperphagic and develop late-onset obesity proves the unique anorexigenic properties of PrRP. Designing and evaluation of PrRP analog(s) with selective anorexigenic properties and searching for PrRP antagonists would contribute to finding the mechanism and possible treatment of obesity and metabolic syndrome. In our recent published study (Maixnerová et al., Peptides (2011)), the PrRP receptor was immunodetected and characterized by saturation binding in three rodent tumor pituitary cell lines. Two naturally occurring analogs, PrRP31 and PrRP20, showed comparable potency in binding, cell signaling and prolactin release in pituitary RC-4B/C cells, as well as caused food intake decrease after intracerebroventricular administration in fasted mice. In the present study, analogs of PrRP20 with C-terminal Phe amide derivatives with modified aromatic...
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The effect of dietary n-3 polyunsaturated fatty acids in the regulation of insulin secretion and glucose homeostasis in mice
Doleželová, Šárka ; Rossmeisl, Martin (advisor) ; Neckář, Jan (referee)
Dietary intake of long-chain polyunsaturated fatty acids of n-3 series (n-3 LC-PUFA), especially eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), exert hypolipidemic effect and prevent cardiovascular disease. One of the main targets of n-3 LC-PUFA is adipose tissue, where they activate so called "metabolic switch", resulting in an improvement of lipid and glucose metabolism. In this report, n-3 LC-PUFA suplementation decreased plasma levels of free fatty acids, accumulation of triacylglyceroles in the liver and improved systemic insulin sensitivity in mice fed a high fat diet. There was also a slight decrease in the -cell mass and lower dysfunction of -cells in response to n-3 LC-PUFA feeding. Incretin hormones are secreted from an intestinal cells in response to the ingestion of food, while they also enhance glucose-stimulated insulin secretion. This thesis also analyzed the effect of dietary n-3 LC-PUFA on insulin secretion induced either by the intraperitoneal or oral administration of glucose. The results demonstrated that n-3 LC-PUFA facilitate glucose clearance in response to its oral administration, an effect that is attributable to increased insulin secretion as compared to the effect of intraperitoneal glucose administration. These results suggest that elevated incretin secretion in response...
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Identifikace peptidického konjugátu s toxickým metabolitem paracetamolu N-acetyl-p-benzochinon iminem
Landíková, Kateřina ; Mladěnka, Přemysl (advisor) ; Vopršalová, Marie (referee)
Acetaminophen (paracetamol) is one of the most used analgesic drug. It is considered as a safe drug, although its administration in large doses can lead to due to known metabolism to impairment of hepatocytes with subsequent necrosis. Acetaminophen is metabolized primarily in the liver where it is converted to inactive compound by conjugation with sulphate or glucoronide. However a small proportion is metabolized by hepatic cytochrome P450 enzymes to a minor but toxic intermediate metabolite N-acetyl-p- benzoquinone imine (NAPQI). This metabolite binds with the macromolecules of the hepatic cells causing dysfunction of the enzymatic systems, structural and metabolic disarray and eventually necrotic cell death. This thesis is a part of larger work intended for preparation polyclonal antibodies which can be used for further research in vivo / in vitro. The objectives of this study are a) the confirmation that NAPQI is the toxic intermediate that can react with free thiol groups and b) the in vitro production of the formed NAPQI-peptide conjugate. Using dexamethasone-induced rat liver microsomal fraction led to the expected production of NAPQI, that was linked on a synthetic peptide containing free thiol group. This adduct was collected and purified by HPLC with gradient elution. The outcome of this...
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